Overcoming skin rejection in composite tissue allotransplantation

Abstract

The application of composite tissue techniques is constrained by the susceptibility of
skin to rejection. The aim of this thesis is to improve our understanding of skin
rejection and find ways to avoid it, in order to enable expansion of the application of
composite tissue transplantation techniques.
The first part of the thesis explores the consequences and mechanism of skin rejection in
rat models. These studies indicate that in the event of allograft failure, there is minimal
damage to the vascular pedicle of a composite tissue allotransplant, even after full
rejection, making retransplantation possible. Furthermore, there is only mild damage to
the recipient tissues, indicating that the second transplant would not be limited in form
or function by recipient tissue bed damage. Finally, the studies indicate that there are
significant differences between the mechanism of rejection of skin in composite tissue
transplants and conventional skin grafts. This means that much of the historical data
relating to skin graft rejection is not necessarily relevant to composite tissue
allotransplantation.
The second part of the thesis uses swine models to explore ways to overcome skin
rejection while avoiding the toxicity of chronic systemic immunosuppression, through
tolerance induction, and site specific therapy. Previous experience in organ and
composite tissue allotransplantation models are analysed to develop the hypothesis that
high-level chimeras are tolerant to vascularised skin allotransplants. In utero and adult
chimerism induction models are then used in an attempt to attain moderate-level
chimeras. A vascularised skin allotransplant model is developed. Finally, the
hypothesis is confirmed with the transplantation of a vascularised skin allotransplant on
to moderate-level chimeras with the achievement of tolerance. In addition, site-specific
therapy is used in an attempt to avoid the side-effects of chronic high-dose systemic
immunosuppression. This led to prolongation of skin survival, but eventual skin
rejection.